DISCLAIMER This slide deck in its original and unaltered format is for educational purposes and is     current as of April...
DISCLAIMERParticipants have an implied responsibility to use the newly acquired information     to enhance patient outcome...
Disclosure of Conflicts of Interest            Michael W.N. Deininger, MD, PhDReported a financial interest/relationship o...
Learning Objectives              L             Upon completion of this activity,           participants should be better a...
Activity Agenda   Activity Overview (5 mins)   Interactive Clinical Debates (50 mins)    – Clinical Debate 1: How Do You...
Interactive Clinical Debates
Clinical Debate 1:    How Do You Choose the OptimalFrontline Therapy for Patients With CML?
CML: Epidemiology and Etiology         In the US, there were 4,870 cases in 2010 and an          expected 5,430 cases in ...
Most CML Patients Are Diagnosed      in the Chronic Phase  Chronic Phase    Blast Phase
Ph Is the Result of t(9;22)(q34;q11)                                                       BCR                            ...
The Cytogenetic Hallmark of CML               Is the Philadelphia Chromosome                                             9...
RT-PCR for BCR-ABL                                                                                                        ...
Monitoring Response:       Sensitivity of Strategies100%       Diagnosis: 1012 Leukemia Cells                             ...
BCR-ABL Kinase Activity Is                  Essential for CML Pathogenesis                                     L          ...
Imatinib Greatly Improved Survival                       in CML-CP (MDACC data)MDACC = The University of Texas M. D. Ander...
Case Study 1            A 60-year-old man presents to his PCP with a             history of left-sided abdominal pain, po...
Laboratory Findings            HGB 10.1 g/dL, WBC 321/nL, platelets 810/nL            Diff: 25% segs, 23% bands, 17% mye...
Case Study 1: Question 1      Which diagnostic tests would you add?             1) FISH for BCR-ABL             2) BCR-ABL...
Case Study 1: Question 2     Which information is not important for decision-     making?            1) Spleen 14 cm      ...
Case Study 1: Question 3    Which of the following are acceptable therapeutic    choices?           1)      Imatinib 400 m...
Case Study 1: Question 4     The patient is started on nilotinib 300 mg BID.     Which two statements about monitoring thi...
Getting Things Right at Diagnosis   The Bare Minimum      History and physical exam: Record spleen size in cm below costa...
Getting Things Right at Diagnosis                       (cont.)       Establish Disease Phase        PLT < 100        Bl...
New CML Risk Score (Eutos Score) for                Patients Treated With Imatinib                                        ...
Is There A Role for Peripheral Blood            FISH for Monitoring Response?          Good correlation between BM, FISH,...
Is There A Role for Peripheral Blood       FISH for Monitoring Response? (cont.)                                          ...
Therapy Standards      Chronic Phase                Advanced Phase        Imatinib                   Dasatinib         ...
Choosing a TKI for First-Line Therapy         Study                       Comparison                         Patients /   ...
OS on First-Line Imatinib                               (IRIS Study)OS = overall survival.Deininger et al, 2009.
IRIS Study: PFS by Molecular Response        at 12 Months on First-Line Imatinib                                          ...
IRIS Study 7-Year Follow-Up: Prognostic Significance      of Molecular Response on First-Line Imatinib                    ...
Not All Data Are As Good As IRIS Data:             Hammersmith Hospital Experience                                        ...
The Community Experience: Only A Minority           of Patients Do Well Enough to Remain on IMCCRe = complete cytogenetic ...
TOPS 24-Mos Update: Study Design                                                                  Imatinib 800 mg/day (400...
TOPS Trial: Imatinib 400 mg Vs. 800 mg:         MMR Rates Over Time (ITT)ITT = intent to treat.Cortes, Baccarani, et al, 2...
Impact of Dose Intensity* on Cumulative            CCyR Rates, 800 mg Arm                                            p = ....
Event-Free Survival* (ITT)                           100                                  90       % Patients Without Even...
Nilotinib in CP1 First-Line:                      3-Year Update of ENESTnd                      Primary end point: MMR at ...
Patient Disposition         Few patients discontinued treatment since the 2-year follow-up         – 4% on nilotinib 300 m...
Cumulative Incidence of MMR                                                   n               100         Nilotinib 300 mg...
Patients With High Sokal Risk Have the          Largest Improvement of MMR by 3 Years                                 p = ...
Cumulative Incidence of CMR                                                    n                 40        Nilotinib 300 m...
Progression to AP/BC: Including Events                                After Discontinuation (ITT Analysis)     Number of P...
Survival After Progression to AP/BC                      100                                      Progressed = 34         ...
Overall Survival   Of 38 total deaths on study, 23 were following progression to AP/BCCI = confidence interval.Saglio et ...
Dasatinib in CP1 First-Line                         2-Year Update of                     DASISION     Treatment-naïve    ...
Cumulative Incidence of MMR                 100        Dasatinib 100 mg QD                                                ...
Cumulative Incidence of CMR                 100        Dasatinib 100 mg QD                            Imatinib 400 mg QD  ...
BCR-ABL Levels at 3 Months*                                100                                        84%                 ...
Cumulative Incidence of CCyR Within 24 Months           According to BCR-ABL Level at 3 Months                    Dasatini...
Transformation to AP/BP According to                   BCR-ABL Level at 3 Months                                10        ...
OS According to BCR-ABL Level                          at 3 Months                       Dasatinib 100 mg QD              ...
Nilotinib and Dasatinib Are Better                Tolerated Than Imatinib                                             Nilo...
ENESTnd Vs. DASISION             Communalities                – Superiority of experimental arm in terms of primary end p...
ENESTnd Vs. DASISION                         An Unallowed Comparison                                              ENESTnd ...
SO325 Trial Design          Randomization             – Imatinib 400 mg/d vs. dasatinib 100 mg/d          Stratification...
BCR-ABL mRNA Level           Median BCR-ABL reduction: Dasatinib 3.3 log vs. imatinib 2.8 log, p = .048Radich et al, 2010.
Clinical Debate 2:How Should the Relapsed/Refractory     CML Patient Be Treated?
Case Study 2   A 49-year-old man with CML has been on imatinib 400 mg    daily for 7 years   He was diagnosed in chronic...
Case Study 2: Question 1Which are the appropriate next steps?  1) Thorough ‘questioning’ for non-compliance  2) Thorough r...
Case Study 2: Question 2A thorough history reveals no evidence for non-compliance and therewas no recent change in medicat...
Case Study 2: Question 3You receive the following results:Normocellular   marrow with micromegakaryocytes, 2% blastsMuta...
Resistance Work-Up              Failure to reach milestones or loss of response                                     No    ...
Therapeutic Milestones on Imatinib         Month             Optimal       Suboptimal    Failure                 3        ...
Therapeutic Milestones on Imatinib                        (cont.)        Month               Optimal       Suboptimal     ...
Therapeutic Milestones on Imatinib                        (cont.)       Month                Optimal       Suboptimal     ...
Therapeutic Milestones on Imatinib                        (cont.)       Month                Optimal       Suboptimal     ...
Therapeutic Milestones on Imatinib                        (cont.)       Month                Optimal       Suboptimal     ...
Therapeutic Milestones on Imatinib                                (cont.)          Month             Optimal        Subopt...
When Is BCR-ABL Mutation                 Analysis Indicated?         Universally Accepted           Failure to reach mile...
Which Increase of BCR-ABL Is the Right       Trigger for BCR-ABL Mutation Screening?    NCCN guidelines: 10-fold    ELN ...
Receiver Operating Characteristic Analysis          to Define Optimal qPCR Trigger                                       1...
What Are the Non-Transplant        Options for Patients With Relapse?                 (Imatinib dose escalation)         ...
Dasatinib: PFS and OS in CML-CP                          After IM Failure                     100                      80 ...
Nilotinib: PFS and OS in CML-CP                       After IM Failure   % Alive                                       Mon...
Patients With Cytogenetic Response to           Second-Line TKIs at 3 Months Do Well         Proportions of patients      ...
Blast Crisis: PFS on Dasatinib               100                         80                   Myeloid Blast      % Not Pro...
Dasatinib for IM Failure in CP: Frequency of Baseline          BCR-ABL Mutations by In Vitro IC50 to Dasatinib     Patien...
Response Rates by In Vitro IC50 to            Dasatinib (excluding T315I)          100         96 94                      ...
Nilotinib Efficacy According to                   Baseline BCR-ABL Mutations in CML-CP                                 Bas...
The “Default” Mutant T315I Is Resistant to        All Currently Approved BCR-ABL TKIsO’Hare et al, 2007.
NCCN Guidelines:       Treatment Options Based on BCR-ABL          Kinase Domain Mutation Status      BCR-ABL KD Mutation ...
Drug Therapy Options for Patients With           Failure on Second-Line TKI Treatment            Third generation ABL kin...
Ponatinib (AP24534): Binding to ABLT315I                             T315I                                                ...
Phase I Study of Ponatinib: Safety                                       N (%; N = 74)      Treatment-Emergent AEs        ...
Response to Ponatinib                                                                             N (%; 55 evaluable)     ...
Treatment Approach for T315I Detection                   and TKI Failure                              T315I detection in t...
Survival After Allogeneic Transplant          in Patients With Imatinib FailureSaussele et al, 2010.
Key Takeaways   Imatinib, nilotinib, and dasatinib are all approved options for    frontline therapy   Nilotinib and das...
Key Takeaways (cont.)   Treatment recommendations are outlined in the NCCN    guidelines for specific BCR-ABL kinase doma...
Community Oncology Clinical Debates: Chronic Myelogenous Leukemia
Community Oncology Clinical Debates: Chronic Myelogenous Leukemia
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Community Oncology Clinical Debates: Chronic Myelogenous Leukemia

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Review a downloadable slide deck by Michael W. N. Deininger, MD, PhD, covering the most clinically relevant new data reported from Community Oncology Clinical Debates: Chronic Myelogenous Leukemia.

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This educational activity has been designed to meet the unique learning needs of hematologists, medical oncologists, oncology fellows, and pathologists involved in the treatment of patients with chronic myelogenous leukemia (CML).

This program is designed to provide hematologists/oncologists with the latest clinical updates on the treatment of patients with CML in the frontline and relapsed settings. Key elements of this program will highlight many of the clinical challenges faced by physicians as they select appropriate therapeutic regimens for their patients. Assisting clinicians in gaining further perspective regarding the importance of response criteria, clinical monitoring of treatment failure/suboptimal response/disease resistance, timing for switching therapy to obtain maximum therapeutic benefit, the significance of BCR-ABL mutational analysis in patients and how this can assist in selecting therapy and designing individualized approaches to managing CML will be important discussion points throughout the symposium.

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  • Prevalence increasing steadily as a result of current therapy options Approximately 4,870 cases in the United States in 2010 (15% of all adult leukemias) and an incidence that increases significantly with age Median age: ~ 67 Risk factors Prior high-dose radiation exposure Exposure to certain organic solvents (benzene) Age Gender (male &gt; female ~ 1.4:1) Majority of cases have no known inciting factor A very small percentage (&lt; 0.1%) of individuals can express BCR-ABL but not develop CML Wrong cell of origin Multiple genetic mutations leading to non-viability of the clone Immune surveillance
  • Purpose of this slide is to note the proper use, advantages, and limitations of Quantitative RT-PCR to diagnose CML
  • FIGURE 2. Survival of patients with early chronic phase chronic myeloid leukemia treated at M. D. Anderson Cancer Center in different eras compared with those treated with imatinib.
  • The staging is complete – this patient has chronic phase CML with a high Sokal risk (2.61).
  • A, C, D are correct: Imatinib 400mg QD, nilotinib 300mg BID and dasatinib 100mg QD are indicated approved for frontline therapy of CML in chronic phase. Given the patient ’s high Sokal risk, you strongly consider a second-line TKI.
  • Figure 2: Correlation between cytogenetics (x-axis) and interphase FISH (y-axis) on bone marrow specimens (r = .98).
  • Update to ENESTnd Larson RA, et al. J Clin Oncol. 2011;29(suppl): Abstract 6511.
  • Last years ASH presentation had PFS (all PD events, not only AP/BC) with 98%, 90% and 75% at 42 months.
  • Fig 4. Overall survival, progression-free survival (PFS), probability of remaining in complete hematologic response (CHR) and of event-free survival (EFS) by intention-to-treat analysis. During follow-up, 11 patients died (one as a result of a leukemia-unrelated cause while still in complete cytogenetic response), 18 patients progressed to accelerated or blastic phases (n 16 blastic phase), and 26 lost their CHR. At 5 years, the probability of survival was 83.2%, of PFS 2.7%, and of remaining in CHR 81.0%. The term EFS as defined for this study reflects the probability of stable cytogenetic response with imatinib at 5 years (62.7%). The figure also shows the probability of loss of major cytogenetic response (MCyR); of the 171 patients who achieved a MCyR 14 lost the response. The 5-year probability of losing a MCyR was 16%. The vertical lines indicate censored patients.
  • Fig 2. Time to first major molecular response (MMR) by treatment arm (intent-to-treat analysis).
  • Only 1 pt in the 400 mg arm had dose intensity ≥ 600 mg 800mg only CCyR rate Month (N) &lt;600mg &gt;=600mg P-value (Fisher ‘ s exact, two-sided) %(n/N) %(n/N) 12 (208) 70(45/64) 90 (129/144) 0.0010 24 (170) 91(40/44) 94(118/126) 0.510 (n.s.)
  • Selected biochemical abnormalities
  • Figure 1.ROC curve for optimally predicting a kinase domain mutation by a rise in BCR-ABL RNA. The quantitative increase in BCR-ABL RNA levels was determined on 233 samples (from 132 patients) with a readable kinase domain (KD) DNA sequence, and a numeric BCR-ABL RNA level on both the sequenced sample and the immediately prior sample. Sensitivity was defined as the number of mutation-bearing samples with a transcript level rise above a moving (fold-change) cutoff threshold divided by the total number of samples with a mutation. Specificity was defined as the number of wild-type samples with a transcript level rise below the same cutoff threshold divided by the total number of samples without a mutation. The Youden index (J) is the vertical distance from each point on the receiver operating characteristic (ROC) curve to the diagonal “chance” line (from 0,0 to 1,1). The maximal J value (Jmax, vertical dotted line), defining the optimal cutoff threshold (2.6-fold transcript level rise) for predicting a concomitant mutation, is denoted, as are the ROC points associated with a 2-, 3-, 5- and 10-fold transcript level rise.
  • Figure 1. Projected survival from 12-month landmark. Patients achieving partial (PCyR) or complete cytogenetic response (CCyR) by 12 months had significantly superior projected survival than patients with minor cytogenetic response (miCyR) or complete hematologic response (CHR; 97% vs 84% at 1 year, P ! .02), who in turn had similar projected survival as patients with hematologic failure (88% at 1 year, P = .89).
  • 24% of imatinib-resistant patients had mutations sensitive to nilotinib (IC50 ≤ 150 nM). These 12 mutations spread across the entire BCR-ABL kinase domain including P-loop, A-loop, and other regions Mutations with IC50 &gt; 150 nM occurred in 13% of imatinib-resistant patients, affecting 3 amino acid residues 15% of imatinib-resistant patients had mutations with unknown in vitro sensitivity to nilotinib.
  • Figure 1. Sensitivity of Bcr-Abl kinase domain mutants to Abl kinase inhibitors. Imatinib: sensitive (1000 nM), intermediate (3000 nM), insensitive (3000 nM). Nilotinib: sensitive (50 nM), intermediate (500 nM), insensitive (500 nM). Dasatinib: sensitive (3 nM), intermediate (60 nM), insensitive (60 nM). aThe IC50 value is the concentration of inhibitor resulting in a 50% reduction in cell viability. 8,12,21,29 †IC50 values are from Burgess et al, 2005.21 ‡IC50 value is from Shah et al, 2002.29 §IC50 value was estimated from Shah et al, 2004.8
  • Besides inhibition of the T315I mutant, AP24534 inhibits proliferation of a wide range of mutants with high selectivity for BCR-ABL cell lines, although mutations that destabilize the inactive conformation of ABL to which AP24534 binds, such as E255V result in modest reductions in binding activity.
  • This slide shows the treatment-emergent adverse events seen in ≥20% of patients.
  • This top of this slide shows the responses achieved among the 38 evaluable patients in chronic phase CML. A CHR was achieved or maintained in 95%. More importantly, a major cytogenetic response was achieved in two thirds of all patients who have had cytogenetic assessment, with a complete cytogenetic response in more than half of all patients. All 9 patients with T315I confirmed at baseline achieved a major cytogenetic response, and it was complete in 8 of them. Responses were somewhat lower among patients without T315I but still more than half achieved a major cytogenetic response and 40% a complete cytogenetic response. The bottom of this slide shows the response of patients with Ph+ disease treated in advanced phases of the disease. A major hematologic response was achieved in 35% of patients, with a major cytogenetic response in 25% of all patients, being complete in half of these. Acknowledging the small numbers, response rates appear to be equivalent for patients with and without T315I. Evaluable patients = There were 55 Evaluable Patients. Definition of the response evaluable population as follows: - Patient has at least one cyto, heme and MMR assessment OR - Patient has discontinued Using the above definition, there are a total of 55 evaluable CML/Ph+ ALL patients in the dataset. Of these 55, 38 are CP CML. Therefore the denominator for response (cyto, heme and MMR) summaries in CP CML would be 38.
  • Figure 2. Survival probability. (A) After allo-SCT. Patients with elective transplantation in first CP (n 20; group I) and patients who underwent transplantation after imatinib failure in first CP (n 36; group II) had a 3-year survival probability of 88% and 94% (CI: 69.3-98.7 and 83.9-99.4), respectively; patients who underwent transplantation in advanced disease (n 28; group III) had a 3-year survival probability of 59% (CI: 38.6-77.5). Tick marks indicate last observation of living patients.
  • Community Oncology Clinical Debates: Chronic Myelogenous Leukemia

    1. 1. DISCLAIMER This slide deck in its original and unaltered format is for educational purposes and is current as of April 2012. All materials contained herein reflect the views of thefaculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice,diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity. Usage Rights This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.
    2. 2. DISCLAIMERParticipants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline forpatient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. DISCLOSURE OF UNLABELED USE This activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. PIM and IMER do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the activity are those of the faculty and do not necessarily represent the views of PIM and IMER. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
    3. 3. Disclosure of Conflicts of Interest Michael W.N. Deininger, MD, PhDReported a financial interest/relationship or affiliation inthe form of: Consultant, Ariad Pharmaceuticals, Inc.,Bristol-Myers Squibb Company, Novartis PharmaceuticalsCorporation; Contracted Research, Bristol-Myers SquibbCompany, Celgene Corporation, Genzyme, Inc.
    4. 4. Learning Objectives L Upon completion of this activity, participants should be better able to: Assess patient and disease characteristics for selecting optimal frontline therapies for patients with CML Identify the characteristics that define a relapsed patient with CML Evaluate the role of mutational analysis for individualizing therapy choices for patients with CML Identify investigational agents in clinical development for patients with CML
    5. 5. Activity Agenda Activity Overview (5 mins) Interactive Clinical Debates (50 mins) – Clinical Debate 1: How Do You Choose the Optimal Frontline Therapy for Patients With CML? – Clinical Debate 2: How Should the Relapsed/Refractory CML Patient Be Treated? Questions & Answers (5 mins)
    6. 6. Interactive Clinical Debates
    7. 7. Clinical Debate 1: How Do You Choose the OptimalFrontline Therapy for Patients With CML?
    8. 8. CML: Epidemiology and Etiology  In the US, there were 4,870 cases in 2010 and an expected 5,430 cases in 2012  15% of all adult leukemias  Incidence increases significantly with age – Median age: ~ 67 years – Prevalence increasing due to current therapy – Most patients present in CP • Majority of CML-related deaths due to progression to AP/BC – 50% of CML patients are asymptomatic at diagnosis  Risk factors – Radiation exposureCML = chronic myeloid leukemia; CP = chronic phase; AP = accelerated phase; BC = blast crisis.NCCN, 2012; Jemal et al, 2010; ACS, 2012; Richardson et al, 2009; Bacarrani, Cortes, et al, 2009.
    9. 9. Most CML Patients Are Diagnosed in the Chronic Phase Chronic Phase Blast Phase
    10. 10. Ph Is the Result of t(9;22)(q34;q11) BCR { q11 BCR ABL Ph 22 { ABL q34 ABL BCR 9 9q+Ph = Philadelphia.
    11. 11. The Cytogenetic Hallmark of CML Is the Philadelphia Chromosome 9q+ Ph 9 22 22q- = Ph chromosomeCourtesy of Christl Müller, Leipzig.
    12. 12. RT-PCR for BCR-ABL Target sequence RT-PCR for BCR-ABL in CML 1 Denaturation: Heat briefly to 1) Qualitative RT-PCR allows for separate DNA strands the diagnosis of CML 2 Annealing: Cool to allow primers Cycle 1 2) Quantitative RT-PCR is used yields 2 molecules to form hydrogen bond with ends Primers of target to quantify the amount of sequence disease 3 Extension: DNA polymerase adds New nucleotides to the nucleo- 3) Allows for the identification of 3” end of each primer tides cryptic BCR-ABL translocations Cycle 2 yields 4 molecules 4) Does not require a bone Cycle 3 yields marrow aspirate for optimal 8 molecules; 2 molecules results (in white boxes) match target sequenceRT-PCR = real time polymerase chain reaction.Suh et al, 2000; Menif et al, 2009; Adapted from Rollins et al, 2000.
    13. 13. Monitoring Response: Sensitivity of Strategies100% Diagnosis: 1012 Leukemia Cells Complete Hematologic Blood Counts Response10% Complete Cytogenetic Cytogenetics Response1% Major PCR Molecular Response0.1% 4.5 log = 0.0032% Complete Undetectable Range Molecular Response
    14. 14. BCR-ABL Kinase Activity Is Essential for CML Pathogenesis L BABL Imatinib (µM) R-A - R BCBC 0.1 0.5 1.0 5.0 10 00 121 BCR-ABL- 22 5 32 p 2 566 2DD 232p KK 3 3 BCR-ABL NALM-1 cells (Ph+)Deininger et al, 1997.
    15. 15. Imatinib Greatly Improved Survival in CML-CP (MDACC data)MDACC = The University of Texas M. D. Anderson Cancer Center.Quintas-Cardama & Cortes, 2006.
    16. 16. Case Study 1  A 60-year-old man presents to his PCP with a history of left-sided abdominal pain, poor appetite, and loss of 10 kg of body weight  PMH is significant for interstitial lung disease with right heart failure and recurrent pleural effusions. A recent EKG shows a QTc interval of 433 ms.  Physical exam reveals splenomegaly (14 cm under left rib cage)PCP = primary care physician; PMH = past medical history; EKG = electrocardiogram.
    17. 17. Laboratory Findings  HGB 10.1 g/dL, WBC 321/nL, platelets 810/nL  Diff: 25% segs, 23% bands, 17% myelocytes, 10% promyelocytes, 8% basophils, 6% monocytes, 4% lymphocytes, 9% blasts  Bone marrow: 7% blasts, 5% basophils  Cytogenetics: 46XY,t(9;22)[20]HGB = hemoglobin; WBC = white blood count; Diff = differentials; segs = segmented neutrophils.
    18. 18. Case Study 1: Question 1 Which diagnostic tests would you add? 1) FISH for BCR-ABL 2) BCR-ABL mutation screening 3) CT abdomen/pelvis ± contrast 4) None of the above 5) All of the aboveFISH = fluorescent in situ hybridization; CT = computed tomography.
    19. 19. Case Study 1: Question 2 Which information is not important for decision- making? 1) Spleen 14 cm 2) WBC 321/nL 3) PLTs 810/nL 4) Peripheral blood blasts 9% 5) History of pleural effusionsPLTs = platelets.
    20. 20. Case Study 1: Question 3 Which of the following are acceptable therapeutic choices? 1) Imatinib 400 mg QD 2) Imatinib 400 mg BID 3) Nilotinib 300 mg BID 4) Dasatinib 100 mg QD 5) Only 1, 2, and 3 6) Only 1, 3 7) Only 1, 3, and 4NCCN, 2012; Sprycel® prescribing information, 2010; Tasigna® prescribing information, 2011;Gleevec® prescribing information, 2010.
    21. 21. Case Study 1: Question 4 The patient is started on nilotinib 300 mg BID. Which two statements about monitoring this patient are incorrect? 1) Blood counts should be monitored weekly until stable 2) Monitoring transaminases and lipase is unnecessary 3) A BMB and karyotyping at 3 months are standard of care 4) Once a complete cytogenetic response has been documented monitoring continues with qPCR only 5) Annual BMB should continue indefinitelyBMB = bone marrow biopsy.
    22. 22. Getting Things Right at Diagnosis The Bare Minimum  History and physical exam: Record spleen size in cm below costal margin  Complete blood count  Bone marrow aspirate with marrow differential  Conventional cytogenetics  Do not treat leukocytosis with imatinib! Optional  Bone marrow trephine  FISH for BCR-ABL Mandatory in case of Ph-  Diagnostic PCR for BCR-ABL negative karyotype  Flow cytometryNCCN, 2012.
    23. 23. Getting Things Right at Diagnosis (cont.) Establish Disease Phase  PLT < 100  Blood or marrow blasts > 15%  Basophils > 20%  Blasts and promyelocytes > 30%  Blasts > 30% Establish Sokal Risk Score = Exp [0.0116 (Age – 4.34)] Low risk < 0.8 + 0.0345 (Spleen – 7.51) + 0.188 [(PLT/700)2 – 0.563] Intermediate risk 0.8–1.2 + 0.0887 (PB blasts – 2.1) High risk > 1.2NCCN, 2012.
    24. 24. New CML Risk Score (Eutos Score) for Patients Treated With Imatinib PFS Requires Confirmation High risk: > 87 Low risk: ≤ 87 Eutos Score = (7 x basophils) + (4 x spleen size)PFS = progression-free survival.Hasford et al, 2011.
    25. 25. Is There A Role for Peripheral Blood FISH for Monitoring Response?  Good correlation between BM, FISH, and karyotyping Distribution of I-FISH Data According to CBA Data Cytogenetic response by I-FISH, n (%) Cytogenetic response by CBA < 1% BCR-ABL+ 1%–5% BCR-ABL+ > 5% BCR-ABL + nuclei nuclei nuclei CCgR (n = 537), no Ph+ metaphases 444 (82.7) 71 (13.2) 22 (4.1) PCgR (n = 77), 1%–35% Ph+ metaphases 7 (9.1) 32 (41.6) 38 (49.3) p Value < .001 < .001 < .001CBA = chromosome banding analysis; CCgR = complete cytogenetic response; I-FISH = interphase fluorescence in situ hybridization;PCgR = partial cytogenetic response.Testoni et al, 2009.
    26. 26. Is There A Role for Peripheral Blood FISH for Monitoring Response? (cont.) % Ph + 100 In Favor 80 r = 0.98  Wide accessibility  Excellent correlation with marrow 60 cytogenetics in patients on IFN-α 40 20 0 Against 0 20 40 60 80 100 % Ph +  IFN-α results not validated in patients on imatinib  Not validated prospectively with clinical end points  Does not detect clonal evolution  Limited sensitivity and dynamic range compared to qPCRIFN = interferon.Le Gouill et al, 2000.
    27. 27. Therapy Standards Chronic Phase Advanced Phase  Imatinib  Dasatinib  Nilotinib  Nilotinib  Dasatinib  Allotransplant  (IFN-α)  (Imatinib)  (Hydroxyurea)  (Hydroxyurea)NCCN, 2012.
    28. 28. Choosing a TKI for First-Line Therapy Study Comparison Patients / Major Author Randomization End Points IRIS IM 400 mg QD 1,106 / 1:1 PFS O’Brien et al, 2003 IFN / Ara-C TOPS IM 400 mg QD 476 / 1:2 MMR at Cortes et al, 2010 12 months IM 400 BID ENESTnd IM 400 mg QD 846 / 1:1:1 MMR at Saglio et al, 2010 NIL 300 mg BID 12 months NIL 400 mg BID DASISION IM 400 mg QD 519 / 1:1 CCyR at Kantarjian et al, 2010 DAS 100 mg QD 12 monthsTKI = tyrosine kinase inhibitor; IM = imatinib; NIL = nilotinib; DAS = dasatinib; MMR = major molecular response;CCyR = complete cytogenetic response.
    29. 29. OS on First-Line Imatinib (IRIS Study)OS = overall survival.Deininger et al, 2009.
    30. 30. IRIS Study: PFS by Molecular Response at 12 Months on First-Line Imatinib 100 90 80 % w ith o u t p r o g r e s s io n 70 60 50 40 Estimated Rate at 54 Months CCyR w it h >≥= 3 log reduction C C y R with 3 lo g r e d u c t io n 30 95% } p = .068 20 10 CCyR w it h << 3 logereduction C C y R with 3 lo g r d u c t io n No CCyR N o C C yR 89% 72% } p < .001 0 0 6 12 18 24 30 36 42 48 54 60 M o n t h s s in c e r a n d o m iz a t io nDeininger et al, 2009.
    31. 31. IRIS Study 7-Year Follow-Up: Prognostic Significance of Molecular Response on First-Line Imatinib p = .014 p = .0006 P=0.001 p = .019Hughes et al, 2010.
    32. 32. Not All Data Are As Good As IRIS Data: Hammersmith Hospital Experience Event: 63% Also off IM due to lack of MCyR or toxicityCHR = complete hematologic response; EFS = event-free survival; MCyR = major cytogenetic response.de Lavallade et al, 2008.
    33. 33. The Community Experience: Only A Minority of Patients Do Well Enough to Remain on IMCCRe = complete cytogenetic response equivalence.Lucas et al, 2008.
    34. 34. TOPS 24-Mos Update: Study Design Imatinib 800 mg/day (400 mg BID; n = 319) 2:1 randomization Imatinib 400 mg/day (n = 157) N = 476 MMR* at 12 months PFS, OS Total 5 years (planned)  Patients enrolled at 103 sites in 19 countries, first patient first visit June 2005  Cytogenetic analysis every 6 months until CCyR, then every 12 months  Molecular analysis by PCR every month for Months 1–3, then every 3 monthsData cut-off of December 31, 2008.*BCR-ABL/control gene ≤ 0.1% utilizing the International Scale.TOPS = Tyrosine Kinase Inhibitor Optimization and Selectivity.Cortes, Baccarani, et al, 2010.
    35. 35. TOPS Trial: Imatinib 400 mg Vs. 800 mg: MMR Rates Over Time (ITT)ITT = intent to treat.Cortes, Baccarani, et al, 2010.
    36. 36. Impact of Dose Intensity* on Cumulative CCyR Rates, 800 mg Arm p = .001 p = .510 100 91 94 90 % Patients Achieving CCyR 80 70 60 < 600 mg ≥ 600 mg 40 20 0 12 Months 24 Months 800 mg Arm*Dose intensity (total amount of drug received divided by the number of days on treatment including days of zero dose)in the first 12 months of treatment. Cortes, Baccarani, et al, 2010.
    37. 37. Event-Free Survival* (ITT) 100 90 % Patients Without Event 80 70 60 EFS at 24 Months 50 95% for Both Arms 40 30 20 400 mg 10 800 mg 0 0 6 12 18 24 30 36 42 Months Since Randomization*EFS; time between randomization and death, progression to AP/BC, loss of MCyR [Ph+ bone marrow cells > 35%] or loss of CHR.Baccarani et al, 2009.
    38. 38. Nilotinib in CP1 First-Line: 3-Year Update of ENESTnd Primary end point: MMR at 12 monthsSaglio et al, 2011.
    39. 39. Patient Disposition Few patients discontinued treatment since the 2-year follow-up – 4% on nilotinib 300 mg BID; 5% on nilotinib 400 mg BID; 6% on imatinibSaglio et al, 2011.
    40. 40. Cumulative Incidence of MMR n 100 Nilotinib 300 mg bid 282 Nilotinib 400 mg bid 281 90 By 3 Years Imatinib 400 mg qd 283 80 73%, p < .0001 By 1 Year 70 % With MMR 55%, p < .0001 70%, p < .0001 60 Δ 17%–20% 50 51%, p < .0001 53% 40 Δ 24%–28% 30 20 27% 10 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months Since RandomizationSaglio et al, 2011.
    41. 41. Patients With High Sokal Risk Have the Largest Improvement of MMR by 3 Years p = .0264 p = .0020 p = .0004 80 77 75 70 67 63 60 54 % With MMR 50 39 40 30 Δ 14% Δ 21% Δ 28% 20 10 n = 103 104 101 101 78 78 0 Low Intermediate High Nilotinib 300 mg BID Imatinib 400 mg QDSaglio et al, 2011.
    42. 42. Cumulative Incidence of CMR n 40 Nilotinib 300 mg bid 282 By 3 Years Nilotinib 400 mg bid 281 32%, p < .0001 Imatinib 400 mg qd 283 % With MR4.5 By 2 Years 30 By 1 Year 26% 11%, p < .0001 28%, p = .0003 20 Δ 13%–17% 21% 15% 10 7%, p < .0001 Δ 6%–10% 10% 0 1% 0 3 6 9 12 15 18 21 24 27 30 33 36 Months Since RandomizationSaglio et al, 2011.
    43. 43. Progression to AP/BC: Including Events After Discontinuation (ITT Analysis) Number of Patients (n) p = .0496 HR = 0.5 [0.2, 1.0] p = .0076 19 HR = 0.3 [0.1, 0.8] 9 6 3.2% 2.1% 6.7% On Core Treatment and After Discontinuation Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD Off treatment progression information was prospectively collected for all patients every 3 months after discontinuationHR = hazard ratio.Saglio et al, 2011.
    44. 44. Survival After Progression to AP/BC 100 Progressed = 34 Died = 23 90 Alive = 11 80 Median Survival 70 10.5 months 60 % Alive 50 40 30 20 10 0 0 6 12 18 24 30 36 Months Since ProgressionSaglio et al, 2011.
    45. 45. Overall Survival  Of 38 total deaths on study, 23 were following progression to AP/BCCI = confidence interval.Saglio et al, 2011.
    46. 46. Dasatinib in CP1 First-Line 2-Year Update of DASISION  Treatment-naïve CML-CP Dasatinib 100 mg QD (N = 259) patients Follow-up (N = 519) Randomized* 5 years  108 centers Imatinib 400 mg QD (N = 260)  26 countries *Stratified by Hasford risk score  Primary end point Confirmed CCyR by 12 months  Other key end points Rates of CCyR and MMR, times to CCyR and MMR, time in CCyR (measure of duration), PFS, OSHochhaus et al, 2011.
    47. 47. Cumulative Incidence of MMR 100 Dasatinib 100 mg QD By 12 months By 24 months Imatinib 400 mg QD 80 65% % of Patients 60 47% Δ 18% 47% 40 Δ 19% 20 28% 0 0 3 6 9 12 15 18 21 24 27 MonthsResponse achieved by 24 months; calculated from randomized subjects with typical BCR-ABL transcripts.Hochhaus et al, 2011.
    48. 48. Cumulative Incidence of CMR 100 Dasatinib 100 mg QD Imatinib 400 mg QD 80 % of Patients 60 40 By 24 months 20 17% 9% 0 0 3 6 9 12 15 18 21 24 27 MonthsResponse achieved by 24 months; calculated from randomized subjects with typical BCR-ABL transcripts.Hochhaus et al, 2011.
    49. 49. BCR-ABL Levels at 3 Months* 100 84% Dasatinib 100 mg QD 80 Imatinib 400 mg QD 64% % of Patients > 1–10% 60 40 36% > 1–10% ≤ 1% 20 16% ≤ 1% 0 n/N 198/235 154/239 37/235 85/239 ≤ 10% > 10% BCR-ABL Level at 3 Months*Calculated from total number of evaluable patients with PCR assessments at 3 months.Hochhaus et al, 2011.
    50. 50. Cumulative Incidence of CCyR Within 24 Months According to BCR-ABL Level at 3 Months Dasatinib 100 mg QD Imatinib 400 mg QD 24 months 24 months 100 98% 100 100% 98% 94% 80 80 % CCyR% CCyR 60 60 64% 40 38% 40 20 20 0 0 0 6 12 18 24 0 6 12 18 24 30 30 Months Months BCR-ABL at 3 months ≤ 1% > 1–10% > 10%Hochhaus et al, 2011.
    51. 51. Transformation to AP/BP According to BCR-ABL Level at 3 Months 10 9.4% Dasatinib 100 mg QD Imatinib 400 mg QD 8.1% 8 % Transformation 6 5.0% 4 3.3% 2.6% 2 1.8% 1.2% 0% 0 n/N 6/235 12/239 2/112 0/32 1/86 4/122 3/37 8/85 Total ≤ 1% > 1–10% > 10% BCR-ABL Level at 3 MonthsHochhaus et al, 2011.
    52. 52. OS According to BCR-ABL Level at 3 Months Dasatinib 100 mg QD Imatinib 400 mg QD 100 100 80 80 % Alive % Alive 60 60 40 BCR-ABL Level at 3 months 40 BCR-ABL Level at 3 months ≤ 1% ≤ 1% 20 > 1–10% 20 > 1–10% > 10% > 10% 0 0 0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42 Months Months For ≤ 10% vs. > 10% comparison: p = .0137 For ≤ 10% vs. > 10% comparison: p = .0081Hochhaus et al, 2011.
    53. 53. Nilotinib and Dasatinib Are Better Tolerated Than Imatinib Nilotinib / Dasatinib Better Nausea IM NIL DAS IMSaglio et al, 2011; Hochhaus et al, 2011.
    54. 54. ENESTnd Vs. DASISION  Communalities – Superiority of experimental arm in terms of primary end point – Equal or better tolerability of experimental arm – High drop out rates – No difference in OS Differences in Design ENESTnd DASISION Risk stratification Sokal Hasford Dose escalation in No Yes experimental arm Assessment of progression On therapy Up to 60 days post d/c of therapyd/c = discontinuation.Larson et al, 2011; Kantarjian et al, 2011.
    55. 55. ENESTnd Vs. DASISION An Unallowed Comparison ENESTnd DASISION CCyR 24 months (%) 87/85a 86a MMR 24 months (%) 62/59b 64a PFS superior in experimental arm Yes No Up to 60 days post d/c Assessment of progression On therapy of therapyResponse by time point.Larson et al, 2011; Kantarjian et al, 2011.
    56. 56. SO325 Trial Design  Randomization – Imatinib 400 mg/d vs. dasatinib 100 mg/d  Stratification – Hasford risk category: Low vs. intermediate vs. high  Number of patients – N = 240 (120/arm)  Assessment schedule – Molecular and hematologic response: 3, 6, 9, 12 mos – Cytogenetic response: 6, 12 mosRadich et al, 2010.
    57. 57. BCR-ABL mRNA Level Median BCR-ABL reduction: Dasatinib 3.3 log vs. imatinib 2.8 log, p = .048Radich et al, 2010.
    58. 58. Clinical Debate 2:How Should the Relapsed/Refractory CML Patient Be Treated?
    59. 59. Case Study 2 A 49-year-old man with CML has been on imatinib 400 mg daily for 7 years He was diagnosed in chronic phase and achieved CCyR after 6 months His qPCR levels on the international scale have fluctuated between 0.09% and 0.4%, but the most recent test showed an increase to 5.6% Comorbidities include diabetes mellitus, polyarthritis, and depression, for which he is managed by 3 additional specialists He is asymptomatic and physical exam is negative
    60. 60. Case Study 2: Question 1Which are the appropriate next steps? 1) Thorough ‘questioning’ for non-compliance 2) Thorough review of co-medications 3) Repeat qPCR 4) Bone marrow biopsy 5) Imatinib drug level testing 6) All of the above 7) Only 1, 2, and 3 8) Only 1, 2, 3, and 5
    61. 61. Case Study 2: Question 2A thorough history reveals no evidence for non-compliance and therewas no recent change in medications. The repeat PCR test reveals alevel of 7.2IS.What is your next step? 1) Bone marrow biopsy with cytogenetics 2) Screening for BCR-ABL kinase domain mutations on a blood sample 3) Screening for BCR-ABL kinase domain mutations on a bone marrow sample 4) Only 1, 2, and 3 5) Only 1 and 2
    62. 62. Case Study 2: Question 3You receive the following results:Normocellular marrow with micromegakaryocytes, 2% blastsMutation screening positive for F359V BCR-ABL mutationCytogenetics 46XY[15]/46XY,t(9;22),inv(3)[5]What is your next step? 1) Increase imatinib to 800 mg BID 2) Switch to nilotinib 400 mg BID 3) Switch to dasatinib 140 mg QD 4) Evaluate for allotransplant 5) Only 2 and 4 6) Only 3 and 4
    63. 63. Resistance Work-Up Failure to reach milestones or loss of response No Complete Diagnostic Work-Up  Physical exam  BMB  Karyotyping  BCR-ABL mutation screenNCCN, 2012.
    64. 64. Therapeutic Milestones on Imatinib Month Optimal Suboptimal Failure 3 <65% Ph+ >95%Ph+ No CHR CCyR or 66-95% 6 1-35% Ph+ better Ph+ Less than 12 MMR or better >35% Ph+ MMR 18 CMR 0% Ph+ >0% Ph+Baccarani et al, 2009.
    65. 65. Therapeutic Milestones on Imatinib (cont.) Month Optimal Suboptimal Failure 3 < 65% Ph+ > 95%Ph+ No CHR 6 CCyR or better 1%–35% Ph+ 66%–95% Ph+ 12 MMR or better < MMR > 35% Ph+ 18 CMR 0% Ph+ > 0% Ph+Baccarani et al, 2009.
    66. 66. Therapeutic Milestones on Imatinib (cont.) Month Optimal Suboptimal Failure 3 < 65% Ph+ > 95%Ph+ No CHR 6 CCyR or better 1%–35% Ph+ 66%–95% Ph+ 12 MMR or better < MMR > 35% Ph+ 18 CMR 0% Ph+ > 0% Ph+Baccarani et al, 2009.
    67. 67. Therapeutic Milestones on Imatinib (cont.) Month Optimal Suboptimal Failure 3 < 65% Ph+ > 95%Ph+ No CHR 6 CCyR or better 1%–35% Ph+ 66%–95% Ph+ 12 MMR or better < MMR > 35% Ph+ 18 CMR 0% Ph+ > 0% Ph+Baccarani et al, 2009.
    68. 68. Therapeutic Milestones on Imatinib (cont.) Month Optimal Suboptimal Failure 3 < 65% Ph+ > 95%Ph+ No CHR 6 CCyR or better 1%–35% Ph+ 66%–95% Ph+ 12 MMR or better < MMR > 35% Ph+ 18 CMR 0% Ph+ > 0% Ph+Baccarani et al, 2009.
    69. 69. Therapeutic Milestones on Imatinib (cont.) Month Optimal Suboptimal Failure 3 Favorable Favorable 6 Favorable outcome outcome outcome likely: uncertain: unlikely: 12 Keep going! Consider Change alternative! strategy! 18Baccarani et al, 2009.
    70. 70. When Is BCR-ABL Mutation Analysis Indicated? Universally Accepted  Failure to reach milestones  Loss of response, progression Controversial  Routine at diagnosis in patients with AP/BC?  Routine monitoring in high-risk patients?  Which is the optimal technology?  Which is the right qPCR trigger?NCCN, 2012.
    71. 71. Which Increase of BCR-ABL Is the Right Trigger for BCR-ABL Mutation Screening?  NCCN guidelines: 10-fold  ELN recommendations: 5-fold  If you live in Australia: 2-fold More than 2-fold rise Stable or decreasing Mutations (%) 34/56 (61) 1/158 (0.6) resistance (%) 31/34 (91) 1/1 (100) No mutations (%) 22/56 (39) 157/158 (99) resistance (%) 13/22 (59) 1/157 (0.6)Brandford et al, 2004.
    72. 72. Receiver Operating Characteristic Analysis to Define Optimal qPCR Trigger 100 90 Jmax (2.6-fold) 80 Sensitivity (%) 70 60 50 40 30 20 10 0 0 10 20 30 40 50 60 70 80 90 100 1 – Specificity (%)Press et al, 2009.
    73. 73. What Are the Non-Transplant Options for Patients With Relapse?  (Imatinib dose escalation)  Nilotinib  Dasatinib  Experimental agentsNCCN, 2012.
    74. 74. Dasatinib: PFS and OS in CML-CP After IM Failure 100 80 % of Patients 60 OS N 12 months 24 months 40 387 97% 94% PFS 20 N 12 months 24 months 387 91% 80% 0 0 3 6 9 12 15 18 21 24 27 30 33 MonthsStone et al, 2007.
    75. 75. Nilotinib: PFS and OS in CML-CP After IM Failure % Alive Months Since Start of TreatmentAdapted from Kantarjian et al, 2007.
    76. 76. Patients With Cytogenetic Response to Second-Line TKIs at 3 Months Do Well Proportions of patients ultimately achieving 12 MMCyR Proportion Alive (%) Time point, response n 12 MMCyR, no. (%) 3 months Minor cytogenetic 15 10 (67) Complete hematologic 42 3 (7) response or hematologic failure 6 months Minor cytogenetic 16 8 (50) Complete hematologic 39 1 (3) response or Months From 12-Month Landmark hematologic failureTam et al, 2008.
    77. 77. Blast Crisis: PFS on Dasatinib 100 80 Myeloid Blast % Not Progressed Lymphoid Blast 60 40 20 0 0 3 6 9 12 15 18 21 24 27 30 MonthsGambacorti et al, 2007.
    78. 78. Dasatinib for IM Failure in CP: Frequency of Baseline BCR-ABL Mutations by In Vitro IC50 to Dasatinib  Patients with resistance or suboptimal response to imatinib Unknown IC50 to dasatinib (n = 74) 9% 38 different BCR-ABL mutations IC50 ≤ 3 nM (n = 248) M244V, G250E, Y253F/H/K, F311L, No BCR-ABL 31% M351T, E355G, mutation F359C/I/V, V379I, (n = 421) L387M, H396P/R 52% < 1% V299L (n = 1) 1% Q252H (n = 6) IC50 > 3 nM 2% F317L (n = 13) (n = 42) 5% 3% E255K/V (n = 25) 2% T315I (n = 20) IC50 > 200 nMMüller et al, 2008.
    79. 79. Response Rates by In Vitro IC50 to Dasatinib (excluding T315I) 100 96 94 IC50 to dasatinib Unknown (n=83) 82 80 ≤3 nM (n=254) 73 >3 nM (n=44) 58 60 54 47 % 43 40 34 34 25 18 20 0 CHR MCyR CCyR MMRMüller et al, 2008.
    80. 80. Nilotinib Efficacy According to Baseline BCR-ABL Mutations in CML-CP Baseline Mutations in Imatinib-Resistant Patients (N = 202) Others* No Mutation T315I 15% IC50-based grouping 3% IC50 ≤ 150 nM F359C/V M244V, L248V, G250E, 5% 45% Q252H, E275K, D276G, E255K/V F317L, M351T, E355A, 4% E355G, L387F, F486S Y253H 4% IC50 > 150 nM 24% Y253H, E255K/V, F359C/V IC50 ≤ 150 nM IC50 > 10,000 nM T315I*Mutations without available IC50 data.Hughes et al, 2009.
    81. 81. The “Default” Mutant T315I Is Resistant to All Currently Approved BCR-ABL TKIsO’Hare et al, 2007.
    82. 82. NCCN Guidelines: Treatment Options Based on BCR-ABL Kinase Domain Mutation Status BCR-ABL KD Mutation Treatment Recommendation T315I HSCT or clinical trial V299L, T315A, F317L/V/I/C Consider nilotinib rather than dasatinib Y253H, E255K/V, F359V/C/ Consider dasatinib rather than nilotinib I Any other mutation Consider high dose imatinib or dasatinib or nilotinibNCCN, 2012.
    83. 83. Drug Therapy Options for Patients With Failure on Second-Line TKI Treatment  Third generation ABL kinase inhibitors – Ponatinib – Bosutinib – DCC-2036  Non-targeted agents – Omacetaxine  Inhibitors of other pathways – Hedgehog/SMO inhibitors – Beta-catenin inhibitorsNational CML Society, 2011; Hu et al, 2009; Jagani et al, 2010; NCCN, 2012.
    84. 84. Ponatinib (AP24534): Binding to ABLT315I T315I N H2N N O NH O Imatinib AP24534 F3C N N OH AP24534 Cellular Proliferation – IC50 (nM) BCR-ABL AP24534 Imatinib Dasatinib Nilotinib Native 0.5 224 0.8 13 T315I 11 > 3,125 > 200 > 2,000O’Hare et al, 2009, 2011.
    85. 85. Phase I Study of Ponatinib: Safety N (%; N = 74) Treatment-Emergent AEs (≥ 20% any grade) Any Grade ≥ Grade 3 Fatigue 26 (35) 0 (0) Constipation 25 (34) 0 (0) Rash 25 (34) 1 (1) Headache 24 (32) 0 (0) Arthralgia 23 (31) 2 (3) Nausea 22 (30) 0 (0) Abdominal pain DLT: Pancreatitis 20 (27) 3 (4) Pyrexia 17 (23) 2 (3) Muscle spasms 16 (22) 0 (0) Vomiting 16 (22) 0 (0) Thrombocytopenia 20 (27) 15 (20) Neutropenia 10 (14) 6 (8) Anemia 14 (19) 6 (8) Data October 15, 2010DLT = dose-limiting toxicity.Cortes et al, 2010.
    86. 86. Response to Ponatinib N (%; 55 evaluable) Best Response Overall T315I* Non-T315I to CML-CP (N = 38) (N = 9) (N = 29) Hematologic CHR** 36 (95) 9 (100) 27 (93) Cytogenetic MCyR 25 (66) 9 (100) 16 (55) CCyR 20 (53) 8 (89) 12 (41) N (%; 55 evaluable) Best Response Overall T315I* Non-T315I to CML-AP (N = 17) (N = 5) (N = 12) Hematologic MHR 6 (35) 1 (20) 5 (42) Cytogenetic MCyR 4 (24) 1 (20) 3 (25) CCyR 2 (12) 0 (0) 2 (17) Data October 15, 2010*Includes only those with T315I status confirmed at study entry.Cortes et al, 2010.
    87. 87. Treatment Approach for T315I Detection and TKI Failure T315I detection in the context of TKI failure Determine disease phase Evaluate for allograft CP AP/BC No Tx candidate Tx candidate Chemotherapy or IA Investigational agent Allograft in remissionNCCN, 2012.
    88. 88. Survival After Allogeneic Transplant in Patients With Imatinib FailureSaussele et al, 2010.
    89. 89. Key Takeaways Imatinib, nilotinib, and dasatinib are all approved options for frontline therapy Nilotinib and dasatinib are superior to imatinib in newly diagnosed CML-CP in surrogate end point (CCyR; MMR; CMR) Improved PFS (statistically significant for nilotinib) Longer follow-up required to ascertain positive effect on OS Good monitoring starts with complete staging at diagnosis Milestones define responses as optimal, suboptimal, or failure and are dependent on the type of therapy (will be updated for new TKIs)
    90. 90. Key Takeaways (cont.) Treatment recommendations are outlined in the NCCN guidelines for specific BCR-ABL kinase domain mutations (eg, dasatinib for F359V/C/I mutations). However: – Ponatinib is the most promising salvage therapy option for patients who failed second-line TKIs, including those with the T315I mutation Allotransplant remains an important salvage option and is a mandatory consideration in case of progression to AP/BC The following targeted agents are options for patients who fail second-line TKIs: Ponatinib, bosutinib, DCC-2036

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